Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes

Stabilization of protein–protein interactions by small molecules

“…Direct binding to this peptidyl-prolyl cis-trans isomerase leads to inhibition of its enzymatic activity explaining the usefulness of CsA derivatives for antiviral therapy [23]. However, the functionally relevant target for the immunosuppressive activity of CsA is not the individual CypA protein but rather its complex with the phosphatase calcineurin (Cn) [24]. Elucidation of the corresponding crystal structure of the ternary complex Cn-CypA-CsA showed how CsA inhibits the enzyme activity of Cn by 'gluing' CypA to the phosphatase and blocking the access to the active site [25].…”

“…The direct target for FK506 is the peptidyl-prolyl isomerase FK506 binding protein (FKBP) [28]. Very similar to CsA, also the effective physiological target of FK506 is not FKBP alone but a complex of the FKBP-bound FK506 and the phosphatase calcineurin [24]. Similar to the situation with CsA-CypA, the FK506-FKBP complex inhibits calcineurin by obstructing the active site of the phosphatase as shown in the crystal structure of the ternary complex published by scientists from Vertex [29].…”

Factors responsible for the Ca2+‐dependent inactivation of calcineurin in brain

“…The specific inhibition of the calmodulin-stimulated protein phosphatase, calcineurin j, by the immunosuppressive drugs, FK506 and cyclosporin A, complexed with their respective binding proteins, cyclophilin and FKBP, suggests that these agents may be competing with endogenous ligands modulating the activity of calcineurin in vivo [10,12]. In an attempt to demonstrate the presence of such regulatory factors we analyzed the activity of calcineurin in crude brain extracts.…”

Everolimus and sirolimus antagonize tacrolimus based calcineurin inhibition via competition for FK-binding protein 12

“…SRL and EVL inhibit mTOR, a kinase with a key function in cell cycle progression [1,2]. Both classes of drugs inhibit enzyme activity only after binding to specific intracellular binding proteins, so called immunophilins [3,4]. CsA binds selectively to the cyclophilin class of immunophilins that are cytosolic peptidyl-prolyl isomerases, while TRL and the mTOR inhibitors (MTIs) bind to the FK506-binding proteins (FKBP) that also exert peptidyl-prolyl isomerase activity [3].…”

“…Both classes of drugs inhibit enzyme activity only after binding to specific intracellular binding proteins, so called immunophilins [3,4]. CsA binds selectively to the cyclophilin class of immunophilins that are cytosolic peptidyl-prolyl isomerases, while TRL and the mTOR inhibitors (MTIs) bind to the FK506-binding proteins (FKBP) that also exert peptidyl-prolyl isomerase activity [3]. SRL, EVL and TRL bind similar FKBPs [5,6], while distinct and selective inhibition of respectively mTOR and CN is observed [7].…”